Phenyl-thiazole-malonic acid derivatives

ABSTRACT

THIAZOLE DERIVATIVES OF THE FORMULA:   X,Y,Z-THIAZOLE   WHEREIN Y OR Z IS LINKED TO THE 2-POSITION OF THE THIAZOLE NUCLEUS, X STANDS FOR HYDROGEN OR ALKYL OF UP TO 3 CARBONS, Y STANDS FOR A PHENYL RADICAL AND Z STANDS FOR A GROUP OF THE FORMULA:   -C(-R1)(-COO-R3)-COO-R2   WHEREIN R1 STANDS FOR HYDROGEN, ALKALI METAL, ALKYL OF NOT MORE THAN 3 CARBONS, DIALKYLAMINOMETHYL OF NOT MORE THAN 5 CARBONS, N-PIPERIDINOMETHYL OR N-MORPHOLINOMETHYL, CHLORINE OR BROMINE, AND R2 AND R3, STANDS FOR HYDROGEN OR ALKYL RADICAL OF NOT MORE THAN 3 CARBONS, PROVIDED THAT WHEN R2 AND R3 STAND FOR HYDROGEN, R1 STANDS FOR HYDROGEN OR AN ALKYL RADICAL OF NOT MORE THAN 3 CARBON ATOMS, AND NON-TOXI PHARMACEUTICALLY-ACCEPTABLE SALTS THEREOF. THESE PHENYL-THIAZOLE-MALONIC ACID DERIVATIVES POSSES ANTI-INFLAMMATORY, ANALGESIC AND ANTI-PYRETIC ACTIVITY. PROCESSES FOR PREPARING THESE COMPOUNDS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME ARE DISCLOSED. A TYPICAL COMPOUNDS IS DIETHYL 4-(4-BROMOPHENYL)THIAZOL-2-YLMALONATE.

United States Patent 3,661,920 PHENYL-THIAZOLE-MALONIC ACID DERIVATIVESWalter Hepworth and Gilbert Joseph Stacey, Macclesfield,

England, assignors to Imperial Chemical Industries Limited, London,England No Drawing. Filed Feb. 17, 1969, Ser. No. 799,963 Claimspriority, application Great Britain, Mar. 22, 1968, 13,989/ 68 Int. Cl.C07d 91/32 US. Cl. 260-302 R 6 Claims ABSTRACT OF THE DISCLOSUREThiazole derivatives of the formula:

wherein Y or Z is linked to the 2-position of the thiazole nucleus, Xstands for hydrogen or alkyl of up to 3 carbons, Y stands for a phenylradical and Z stands for a group of the formula:

R1 JJCO2R2 wherein R stands for hydrogen, alkali metal, alkyl of notmore than 3 carbons, dialkylaminomethyl of not more than carbons,N-piperidinomethyl or N-morpholinomethyl, chlorine or bromine, and R andR stand for hydrogen or alkyl radical of not more than 3 carbons,provided that when R and R stand for hydrogen, R stands for hydrogen oran alkyl radical of not more than 3 carbon atoms, and non-toxicpharmaceutically-acceptable salts thereof. Thesephenyl-thiazole-rnalonic acid derivatives possess anti-inflammatory,analgesic and anti-pyretic activity. Processes for preparing thesecompounds, and pharmaceutical compositions containing the same aredisclosed. A typical compounds is diethyl 4-(4-bromophenyl)thiazol-Z-ylmalonate.

This invention relates to new heterocyclic compounds and moreparticularly it relates to new thiazole derivatives which haveanti-inflammatory, analgesic and antipyretic activity.

According to the invention we provide compounds which in one of theirtautomeric forms are thiazole derivatives of the formula:

wherein Y or Z is linked to the 2-position of the thiazole nucleus, Xstands for hydrogen or an alkyl radical of not more than 3 carbon atoms,Y stands for the phenyl radical or a phenyl radical which is substitutedby not more than two halogen atoms selected from fluorine, chlorine andbromine atoms, and Z stands for a group of the formula:

R1 --CO:R

wherein R stands for hydrogen, an alkali metal atom, an alkyl radical ofnot more than 3 carbon atoms, a dialkylaminomethyl radical of not morethan 5 carbon atoms, the N-piperidinomethyl or N-morpholinomethylradical, or a chlorine or bromine atom, and R and R which may be thesame or ditferent, stand for hydrogen or an alkyl radical of not morethan 3 carbon atoms, provided that when R and R stand for hydrogen, Rstands for hydrogen or an alkyl radical of not more than 3 carbon atoms,and non-toxic, pharmaceutically-acceptable salts thereof.

The thiazole nucleus is numbered as follows:

a I4 r l s 1 It is to be understood that, in the thiazole derivatives ofthis invention, either Y is linked to position 2 and Z is linked toposition 4 or 5, or Z is linked to position 2 and Y is linked toposition 4 or 5. This general situation also obtains throughout thisspecification, thus it obtains in the case of the intermediates used inmaking the thiazole derivatives of the invention. It is also to beunderstood that, in the case where Z is in the 2-position of thethiazole nucleus and R stands for hydrogen, the compounds of theinvention may exist predominantly in the tautomeric A thiazoline form.However, for convenience, in this specification all the compounds of theinvention will be named as thiazole derivatives.

As a suitable value for X there may be mentioned, for example, hydrogenor the methyl radical.

As a suitable value for R there may be mentioned, for example, hydrogenor the methyl radical.

As a suitable value for R there may be mentioned, for example, hydrogen,the sodium or bromine atom, or the methyl, dimethylaminomethyl,N-piperidinomethyl or N- morpholinomethyl radical.

As a suitable value for R or R there may be mentioned, for example,hydrogen or the methyl or ethyl radical.

As suitable salts in the case where R and/or R stands for hydrogen theremay be mentioned, for example, a salt formed from that carboxylic acidand a non-toxic, pharmaceutically-acceptable cation, for example analkali metal salt, an alkaline earth metal, salt, or an aluminium orammonium salt, or a salt with a non-toxic, pharmaceutically-acceptableorganic base. In cases where the thiazole derivative of the invention issufiiciently basic, suitable salts are non-toxic pharmaceutically-acceptable acid-addition salts.

Preferred specific compounds of the invention are dimethyl or [4 (4bromophenyl)thiazol 2 yl] ccmethylmalonate, dimethyl2-(4-chlo1ophenyl)thiazol-4- ylmalonate, the a-sodium derivative ofdimethyl 2-(4- chlorophenyl)thiazol-4-ylmalonate, and dimethyl a-[2-(4-chlorophenyl) thiazol-4-yl] -a-methylmalonate.

According to a further feature of the invention We provide a process forthe manufacture of compounds which in one of their tautomeric forms havethe formula:

X X S wherein Y or ----CH(CO R).CO R is linked to the 2- position of thethiazole nucleus, and X stands for hydrogen or an alkyl radical of notmore than 3 carbon atoms, Y has the meaning stated above, and R and Rwhich may be the same or different, stand for an alkyl radical of notmore than 3 carbon atoms, and non-toxic pharmaceutically-acceptableacid-addition salts thereof, which comprises reacting a compound of theformula wherein Y or -CH R is linked to the 2-position of the thiazolenucleus, and, when R stands for hydrogen, CH R is linked to the2-position of the thiazole nucleus, and X and Y have the meanings statedabove, and R stands for hydrogen or a CO R group wherein R has themeaning stated above, with a carbonate of the formula R*O.CO.OR whereinR has the meaning stated above, and sodium or potassium or a hydride,amide or C alkoxide thereof.

Suitable values for R and R are those stated above in respect of R and Rbut excluding hydrogen. The reaction may be carried out in an excess ofthe carbonate used as reactant and/or in an inert solvent, for exampleether. The reaction may optionally be carried out under the influence ofheat, for example at a temperature of 70- 150 C.

According to a further feature of the invention we provide a process forthe manufacture of compounds which in one of their tautomeric forms hasthe formula:

X R. i Y mote-6 R502 wherein X, Y, R and R have the meanings statedabove, R stands for hydrogen or an alkyl radical of not more than 3carbon atoms, and non-toxic pharmaceuticallyacceptable acid-additionsalts thereof, which comprises reacting a compound of the formula:

wherein R R and R have the meanings stated above, and M stands for analkali metal atom.

The reaction may be carried out in an excess of the appropriate malonatederivative and/or in an inert solvent, for example dimethylformamide.The reaction may optionally be accelerated or completed by theapplication of heat.

According to a further feature of the invention we provide a process forthe manufacture of compounds of the formula:

N Alk v-h -qiz-ooia XXS OzR wherein Y or CAlk(Co R ).CO R is linked tothe 2- position of the thiazole nucleus, and X, Y, R and R have themeanings stated above, and Alk stands for an alkyl radical of not morethan 3 carbon atoms, an nontoxic pharmaceutically-acceptableacid-addition salts thereof, which comprises alkylating a compound whichis one of its tautomeric forms has the formula:

X S 601R X wherein Y or -CH(CO R )-CO R is linked to the 2- position ofthe thiazole nucleus, and X, Y, R and R have the meanings stated above,so as to introduce an alkyl radical of not more than 3 carbon atoms intothe a-position.

The alkylation may be carried out by the interaction of an alkali metalderivative of the appropriate thiazole derivative with an alkyl halideof not more than 3 carbon atoms, for example methyl iodide. An organicsolvent, for example dimethylformamide, may optionally be present.

According to a further feature of the invention we pro vide a processfor the manufacture of compounds of the formula:

X s JJOQRJ X wherein Y or CM(CO R -CO R is linked to the 2- position ofthe thiazole nucleus, and X, Y, R and R have the meanings stated aboveand M stands for an alkali metal atom, which comprises reacting acompound of the formula:

wherein Y or CH(CO R -CO R is linked to the 2- position of the thiazolenucleus, and X, Y, R and R have the meanings stated above, with analkali metal or a hydride, amide or C alkoxide thereof.

The reaction is conveniently carried out in an organic solvent, forexample ether.

According to a further feature of the invention we provide a process forthe manufacture of compounds which have the formula:

wherein Y or --CR (CO R -CO-,,R is linked to the 2- position of thethiazole nucleus, and R stands for a dialkylaminomethyl radical of notmore than 5 carbon atoms or the N-piperidinomethyl or N-morpholinomethylradical, and X, Y, R and R have the meanings stated above, and non-toxicpharmaceutically-acceptable acid addition salts thereof, which comprisesreacting a compound which in one of its tautomeric forms has theformula:

N H Y-fib-o 01114 X S (BOERE X N I Hal y-fkqql-com XS com wherein Y orCHal(CO R )-CO R is linked to the 2-position of the thiazole nucleus,and X, Y, R and R have the meanings stated above, and Hal stands for achlorine or bromine atom, which comprises reacting a compound which inone of its tautomeric forms has the formula:

wherein Y or CH(CO R -CO R is linked to the 2- position of the thiazolenucleus, and X, Y, R and R have the meanings stated above, withchlorine, bromine, N-bromosuccinimide or phenyltrimethylammoniumperbromide.

The last named reaction may be carried out in an inert solvent, forexample ether or tetrahydrofuran. The reaction involving chlorine orbromine itself may be carried out in glacial acetic acid in the presenceof an alkali metal acetate.

According to a further feature of the invention we provide a process forthe manufacture of compounds of the formula:

wherein X and Y have the meanings stated above, and R stands forhydrogen or an alkyl radical of not more than 3 carbon atoms, whichcomprises reacting a corresponding alkali metal salt, alkaline earthmetal salt, aluminium salt or ammonium salt with an acid at a relativelylow temperature.

As a suitable acid there may be mentioned an inorganic acid, for examplehydrochloric acid, or a sufficiently strong organic acid, for exampleacetic acid. The reaction should be carried out at a relatively lowtemperature, for example at or below 0 C., in order to preventdecomposition of the product.

It is to be understood that the non-toxic, pharmaceutically-acceptablesalts of the invention may be obtained by means of conventionalprocedures.

It is also to be understood that the starting materials used in theabove process can be obtained by known general methods.

According to a further feature of the invention we providepharmaceutical compositions comprising at least one compound which inone of its tautomeric forms is a thiazole derivative of the formula:

N YHqZ wherein Y or Z is linked to the 2-position of the thiazolenucleus, and X, Y and Z have the meanings stated above, or a non-toxicpharmaceutically-acceptable salt thereof, and a non-toxicpharmaceutically-acceptable diluent or carrier.

The pharmaceutical compositions may, for example, be in the form oftablets, pills, capsules, suppositories, non-sterile aqueous ornon-aqueous solutions or suspensions, sterile injectable aqueous ornon-aqueous solutions or suspensions, creams, lotions, or ointments.These compositions may be obtained in conventional manner usingconventional excipients. The compositions may optionally contain, inaddition to at least one of the compounds which characterise thisinvention, at least one known agent having anti-inflammatory oranalgesic activity, for example aspirin, paracetamol, codeine,chloroquine, phenylbutazone, oxyphenbutazone, indomethacin, mefenamicacid, flufenamic acid, ibufenac, or an anti-inflammatory steroid, forexample prednisolone. Those compositions intended for oraladministration may, in addition, optionally contain an anti-cholinergicagent, for example homatropine methyl bromide, and/ or an antacid,

for example aluminum hydroxide, or a uricosuric agent, for exampleprobenecid. Those compositions suitable for topical application may, inaddition, optionally contain a vasodilating agents, for exampletolazoline, or a vasoconstricting agent, for example adrenaline; a localanaesthetic, for example amethocaine, a counter-irritant, for examplecapsicum; and/or at least one agent chosen from the following classes ofsubstances: anti-bacterial agents, which includes sulphonamides andantibiotics having antibacterial action, for example neomycin;antifungal agents, for example hydroxyquinoline; anti-histamic agents,for example promethazine; and rubefacient agents, for example methylnicotinate.

The invention is illustrated but not limited by the following examples:

EXAMPLE 1 A mixture of sodium hydride (4.8 g., weighed as a 50%dispersion in oil, and subsequently washed free from oil by decantationwith light petroleum), diethyl carbonate (36 ml.), and4-(4-bromophenyl)-2-methy1- thiazole (5.1 g.) was stirred under refluxfor 3 hours in an oil-bath at 135140 C. The mass, which was then of athick consistency, was treated with suflicient ethanol to destroy theexcess of sodium hydride. Water (50' ml.) was added, and the solidpresent was extracted with chloro (3X50 ml.), the extract being washedin turn with dilute hydrochloric acid (40 ml.), aqueous sodium carbonate(10% w./v.), and water (40 ml.). The chloroform solution was dried withanhydrous sodium sulphate, and evaporated down to give a residue whichwas crystallised from ethanol and yielded diethyl4-(4-bromophenyl)thiazol-2-ylmalonate, MJP. 130-131 C.

EXAMPLE 2 A mixture of sodium hydride (7.2 g., see Example 1 forprocedural details), dimethyl carbonate (52 ml.), and4#(4-bromophenyl)2-methylthiazole (7.6 g.) was stirred under reflux for6 hours in an oil-bath at 105-1 15 C. The resulting thick suspension wascooled, and any excess of sodium hydride was destroyed by addition ofmethanol. Water ml.), and sufficient hydrochloric acid to give a pH of7, were added. The solid present was extracted into methylene dichloride(3X80 ml.). The extract was washed with dilute aqueous sodium carbonate(10 w./v., 50 ml.) and then with water (50 ml.). It was dried withanhydrous sodium sulphate, and evaporated down to leave a solid, whichwas triturated with ethyl acetate (50 ml.) to remove unchanged startingmaterial. Crystallisation of the residue from chlorobenzene, in thepresence of decolourising carbon, gave dimethyl4-(4-bromophenyl)thiazol-Z-ylmalonate, Ml. l73-174 C.

EXAMPLE 3 Dimethyl 4-(4-bromophenyl) thiazol-Z-ylmalonate 1.85 g.) wasadded to a suspension of sodium hydride (0.24 g., see Example 1 forprocedural details) in dry dimethylformamide (15 ml.), and stirred for30 minutes at 35 C. Methyl iodide 1.25 ml.) was then added, and stirringat 35 C. was continued for a further 1 hour. The mixture was cooled to10 C. and diluted carefully with water (30 ml.). Traces of methyl iodidewere distilled ofi' under reduced pressure, and the solid was collectedby filtration, washed with Water, and dried in vacuo over phosphoruspentoxide. Crystallisation from light petroleum (B.P. 60- 80" C.) gavedimethyl u-[4-(4-bromophenyl) thiazol-2- yl]-u-methylmalonate, M.P.64'65.5 C.

EXAMPLE 4 Diethyl malonate (6.1 ml.) was added to a suspension of sodiumhydride (1.9 g.; see Example 1 for procedural details) in drydimethylformamide (25 ml.) and stirred for 30 minutes. 2Bromo-4-(4-bromophenyl)-thiazole (5.4 g.) was then added. The mixturewas stirred and heated under reflux for 4 hours in an oil-bath at145-155 C. Water (50 ml.), and sufficient hydrochloric acid to give a pHof 7, were added to the cooled mixture, and the precipitated solid wascollected by filtration, and washed successively with water (40 ml.) andether (50 ml.) to remove coloured contaminants. The solid dissolved inmethylene dichloride (100 ml.), and the solution was successively washedwith aqueous sodium carbonate (10% w./v., 30 ml.) and water (30 ml.).The solution was dried over anhydrous sodium sulphate, treated withdecolourising carbon, filtered and evaporated to dryness. Twocrystallisations from ethanol gave diethyl 4 (4bromophenyl)thiazol-Z-ylmalonate, identical in physical properties withmaterial prepared by the procedure described in Example 1.

EXAMPLE Sodium hydride (0.26 g.) was suspended in dry ether (60 ml.) anda solution of methyl 2-(4-chlorophenyl) thiazol-4-ylacetate (2.6 g.) indry ether (60 ml.) was added dropwise with stirring over 30 minutes. Asolution of dimethyl carbonate (1.8 g.) in dry ether ml.) was added overminutes, and the resulting mixture was stirred under nitrogen for 16hours at room temperature. A further quantity of sodium hydride (0.26g.) was then added and the mixture was stirred for a further 3 hours.The mixture was filtered, and the residue was washed with ether and thenstirred with 2 N-aqueous sodium hydroxide (30 ml.) and filtered. Therewas thus obtained as solid residue the a-sodium derivative of dimethyl2-(4-chlorophenyl)thiazol-4-ylmalonate dihydrate, M.P. 133 C.

This sodium derivative (2 g.) was suspended in a mixture of water ,(50ml.) and ether (50 ml.), and N-aqueous hydrochloric acid (50 ml.) wasadded with vigorous stirring. The ether layer was separated, washed wellwith water, dried with anhydrous magnesium sulphate, and evaporated todryness. The residue was crystallised from n-hexane to give dimethyl 2(4-chlorophenyl triazol-4- ylmalonate, M.P. 46 C.

EXAMPLE 6 A solution of bromine (0.8 g.) in glacial acetic acid (10 ml.)was added over 10 minutes to a stirred mixture of dimethyl2-(4-chlorophenyl)thiazol-4-ylmalonate (1.6 g.) and anhydrous sodiumacetate (0.82 g.) in glacial acetic acid ml.) at room temperature. Afterminutes, the mixture was poured into water (100 ml.), and the productwas extracted into ether (50 ml.). The ethereal extract was dried overanhydrous magnesium sulphate, the solvent was evaporated in vacuo, andthe residue was crystallised from cyclohexane. There was thus obtaineddimethyl a-bromo-u-[2-,(4-chlorophenyl)thiazol- 4-yl]malonate, M.P.110-111 C.

EXAMPLE 7 An aqueous solution of dimethylamine (2.8 ml.) was added to astirred solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate (8g.) in methanol (16 ml.). To the resulting suspension there was addeddropwise a 36% w./v. aqueous solution of formaldehyde (2.16 ml.) over 5minutes at room temperature. After stirring the mixture for one hour,the product was collected by filtration and washed with aqueous ethanol.There was thus obtained dimethyl a-[2-(4-chloropheny1)-thiazol-4-yl]-a-dimethylaminomethylmalonate, M.P. 95-96" C.

EXAMPLE 8 A mixture of sodium hydride (3.4 g.), 50% dispersion-seeExample 1 for procedural details), dimethylcarbonate (21 ml.), and5-(4-chlorophenyl)-2-methylthiazole (2.9 g.) was stirred under reflux inan oil-bath at 105-115 C. for 4 /2 hours. The mixture, which had becomevery thick, was cooled, diluted with ether (25 ml.), treated withsufficient methanol to destroy any remaining sodium hydride, and mixedwith water (50 ml.).

Sufiicient acetic acid was added to give a pH of 7, and the solidpresent was collected by filtration, washed well with water and dried.Crystallisation from chlorobenzene in the presence of decolourisingcarbon gave dimethyl 5- (4 chlorophenyl)thiazol 2 ylmalonate, M.P. 212.5214 C.

In a similar fashion, but using diethyl carbonate instead of dimethylcarbonate, and a reaction time of 1% hours at -140 0., there wasobtained diethyl 5-(4-chl0rophenyl)thiazol-Z-ylmalonate, M.P. 161-1615C. (crystallised from n-propanol) The 5-(4-chlorophenyl)-2-methylthiazo1e used as starting material was obtainedas follows:

5 (4-chlorophenyl)-2-methyloxazole (7.75 g.M.P. 74.5-75.5 C.; preparedby the action of sodium azide and sulphuric acid on4-chlorobenzoylacetone by an adaptation of a known procedure for thepreparation of 2-methyl-5-phenyloxazole) was intimately mixed withfinely-powdered phosphorus pentasulphide (8.9 g.) and heated directlyover a flame to give a dark, viscous melt. After 5 minutes, the melt wasallowed to cool, and the mixture was boiled with aqueous 4N-hydrochloric acid ml.) for 20 minutes. The resultant suspension wascooled and filtered, and the filtrate was clarified by addition ofkieselguhr, and then filtered again. Aqueous 40% sodium hydroxide wasadded slowly to the filtrate, which was cooled to 10-20 C. and stirredduring the addition. When the pH had reached 7, the resultingprecipitate was collected by filtration, and was washed well with water.It was crystallised from a 4:1 mixture of methanol and water to give5-(4-chlorophenyl)-2-methylthiazole, M.P. 83.584.5 C.

EXAMPLE 9 Dimethyl 5-(4-chloropheny1)thiazol-2-ylmalonate (3.9 g.) wasadded to a suspension of sodium hydride ,(0.6 g., 50% dispersion,treated as in Example 1) in dry dimethylformamide (35 ml.), and themixture was stirred at 30- 35" C. for 30 minutes. Methyl iodide (7.1 g.)was added, and stirring at 30-35" C. was continued for a further hour.The liquor was then cooled to 15 C., and diluted with water (50 ml.).Extraction with ether (3 X50 ml.) gave a solution which was washed withwater (3 X40 ml.) dried over anhydrous sodium sulphate, and evaporatedto dryness. The residual solid was a mixture which was separated intoits two components by passing a solution of the material in benzene downan alumina column (200 g. of alumina). One compound passed throughreadily, and was recovered by evaporation of the eluate and crystallisedfrom acetonitrile to give dimethyl a-[5,(4-chlorophenyl)-thiazol-2-yl]-a-methylmalonate, M.P. 129- 130" C. Thesecond component, eluted from the column with chloroform, was5-(4-chlorophenyl)-2- [di(methoxycarbonyl) methylene] -1-methyl-A-thiazoline.

EXAMPLE 10 The a-sodium derivative of dimethyl2-(4-chlorophenyl)tbiazol-4-ylmalonate (2.5 g.) was suspended in drydimethylformamide (20 ml.), and methyl iodide (1 ml.) was added. Themixture was stood at 1520 C. for 16 hours. Water (200 ml.) was added,and the mixture was extracted with ether (100 ml.). The ethereal layerwas washed with water, dried over anhydrous magnesium sulphate, filteredand evaporated to dryness, giving dimethyl u- [2- (4-chlorophenyl)thiazol-4-yl] -a-methylmalonate was obtained as a yellow oil,examination by N.M.R. shows a methyl signal at 63.7 p.p.m. and methylester signal at 51.65 p.p.m.

EXAMPLE 11 A mixture of methyl2-(4-chlorophenyl)-4-methylthiazol-S-ylacetate (14.6 g.), sodium hydride(2.5 g.) and dimethylcarbonate (50 ml.) was stirred at a bathtemperature of l001l0 for 3 /2 hours. Methanol (10 ml.) was added todestroy the excess of sodium hydride, and immediately afterwards 10%v./v. aqueous acetic acid (200 ml.) was added. The resultant mixture wasextracted with 3 separate portions of chloroform (50 ml. each). Thecombined chloroform extracts were washed with water (3X 100 ml.), driedover anhydrous magnesium sulphate, filtered and evaporated to dryness.The resultant solid residue was crystallised from cyclohexane to givedimethyl 2-(4-chlorophenyl)-4-methylthiazol-5- ylmalonate, M.P. 140-141C.

EXAMPLE 12 A solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate(3.25 g.) and piperidine (1 ml.) in methanol (15 ml.) was stirred at 15C., and a 36% w./v. aqeous solution of formaldehyde (1 ml.) was addedover minutes. After hours, water (5 ml.) was added, and after a further12 hours a solid had precipitated. This solid was collected byfiltration and washed with 50% aqueous methanol (10 ml.). There'was thusobtained dimethyl ct- [2- (4-chl0rophenyl thiazol-4-yl] -a-(N-piperidinomethyl)malonate, M.P. 9091 C.

In similar manner but using morpholine (1 ml.) instead of piperidinethere was obtained dimethyl a-[2-(4- chlorophenyl)thiazol-4-yl] a(N-morpholinomethyl) malonate, M.P. 124-126 C.

EXAMPLE 13 A mixture of methyl 2-(2,4-dichlor0phenyl)thiazol-4-ylacetate (1.6 g.), sodium hydride (0.7 g.) and dimethyl carbonate (10ml.) was stirred under reflux (bath temperature 100-110 C.) for 3 hours.The mixture was cooled, and methanol (5 ml.) was added to destroy theexcess of sodium hydride. An aqueous solution of 10% v./v. acetic acid(50 ml.) was added, and the resultant mixture was extracted with ether(3X 50 ml.). The combined ethereal extracts were washed with water (3 X100 ml.), dried over anhydrous magnesium sulphate, filtered, andevaporated to dryness. The residue was crystallised from petroleum ether(B.P. 60-80 C.) to give dimethyl 2-(2,4-dichlorophenyl)thiazol4-ylmalonate, M.P. 92-94" C.

EXAMPLE 14 Diethyl a-methylmalonate (3.5 g.) was added to a suspensionof sodium hydride (0.96 g., 50% dispersion, treated as in Example 1) indry dimethylformarnide (12 ml.), and the mixture was stirred at ambienttemperature until evolution of hydrogen and ceased. 2-bromo-4-(4-bromophenyl)thiazole (3.2 g.) was added, and the mixture wasstirred in an oil-bath at 110 C. for 1 /2 hours. The solution wascooled, diluted with water (50 ml.) was extracted thoroughly withmethylene dichloride (3X 50 ml.). The extract was washed with water (3X30 ml.), dried over anhydrous sodium sulphate, and evaporated to give anoil. This was submitted to thin layer chromatography on silica, withbenzene as developing solvent. Elution of the appropriate band withether and recovery by evaporation gave diethyla-[4-(4-bromophenyl)thiaz0l-2-yl]-a-methy1malonate which wascrystallised from petroleum ether (B.P. 4060 C.), and had M.P. 45-46" C.7

EXAMPLE A solution of dimethyl 2-(4-chlorophenyl)thiazol-4-y1- malonate(0.65 g.) in dimethylformamide (10 ml.) was stirred at 0-5 C. and 10N-aqueous sodium hydroxide (0.6 ml.) was added. After stirring for 12hours, dry ether ml.) was added. The resulting precipitate was collectedby filtration and washed with dry ether (20 ml.) to give disodium2-(4-chlorophenyl)thiazol-4-ylmalonate, M.P. 296 C. (decomposition).This salt was dissolved in water (20 ml.), and glacial acetic acid wasadded at a temperature below 10 C. until precipitation ceased. Themixture was filtered to give 2-(4-chlorophenyl)thiazol-4-ylmalonic acid.This melted with decomposition over the range 50-70 C. (to give2-(4-chlorophenyl)thiazol-4-ylacetic acid, M.P. 154.5 C.).

10 EXAMPLE 16 A mixture of dimethyl a-[4-(4-bromopheny1)thiazo1-2-yl]-a-methylmalonate g.) and maize starch (300 g.) was granulated with asuflicient quantity of 10% w./v. starch paste. The granules were passedthrough a 20- mesh screen, and were dried at a temperature not exceeding50 C. The dried granules were blended with magnesium stearate (4 g.) andthen compressed into tablets containing from 50 to 250 mg. of activeingredient. There were thus obtained tablets suitable for oral use fortherapeuticpurposes. 1

The thiazole derivatives of the invention are active in a test (Adjuvantinduced arthritis in rats; Newbould, Brit. J. Pharmacol. Chemotherap,1963 21, 127-136) which is standard in the art for testing foranti-inflammatory activity. It is well known and accepted in the artthat non-steroidal anti-inflammatory compounds exhibit analgesic .andantipyretic activity. Accordingly, as the compounds of the invention arenon-steroidal anti-infiammatory compounds, it is reasonable to concludethat they possess analgesic and antipyretic activity.

The compounds of the invention are useful in the treatment ofwarm-blooded animals (including mammals) and for this purpose werecommend that one of said compounds be administered orally as asuitable dosage unit form, for example a tablet or capsule, and that thedaily dosage be in the range 0.75 to 15 mg. per kg. of host. Inparticular, when one of said compounds is used for the treatment of manwe recommend that it be administered orally as a suitable dosage unitform, for example a tablet or capsule, at a total daily dose of 50 to1000 mg. of said compound per 70 kg. man.

What we claim is:

1. A compound which in one of its tautomeric forms is a thiazolederivative of the formula:

wherein Y or Z is linked to the 2-position of the thiazole nucleus, Xstands for hydrogen or an alkyl radical of not more than 3 carbon atoms,Y stands for the phenyl radical which is substituted by not more thantwo halogen atoms selected from fluorine, chlorine and bromine atoms,and Z stands for a group of the formula:

2. A compound as claimed in claim 1 which in one of its tautomeric formsis a thiazole derivative of the formula:

N We wherein Y or Z is linked to the 2-position of the thiazole nucleus,X stands for hydrogen or the methyl radical, Y

11 has the meaning stated in claim 1, and Z stands for a group of theformula:

wherein R stands for hydrogen, the sodium or bromine atom, or themethyl, dimethylaminomethyl, N-piperidinomethyl or N-morpholinomethylradical, and R and R which may be the same or different, stand forhydrogen or the methyl or ethyl radical, or an alkali metal salt,alkaline earth metal salt, aluminum or ammonium salt, or salt with anon-toxic pharmaceutically-acceptable organic base, or a non-toxicpharmaceutically-acceptable acid-addition salt.

3. Dimethyl a-[4 (4-bromophenyl)thiazol- 2- yl]-amethylmalonate.

4. Dimethyl 2-'(4-chloropheny1)thiazol-4-ylmalonate.

5. The a-sodium derivative of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate.

UNITED STATES PATENTS 9/1969 OMant 260307 OTHER REFERENCES Conant,Chemistry of Organic Compounds (1934), p. 269.

LoWy et al., Introduction to Organic Chemistry, Ne York, 1945, p. 213.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

